title: Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs.
abstract: Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. Although the origin of LAM cells is unknown, several features of LAM provide clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas and might lead to novel therapeutic strategies for both diseases.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Hen
authors.initials: H
authors.lastname: Prizant
authors.forename: Aritro
authors.initials: A
authors.lastname: Sen
authors.forename: Allison
authors.initials: A
authors.lastname: Light
authors.forename: Sung-Nam
authors.initials: SN
authors.lastname: Cho
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hammes
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D007889:Leiomyoma / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009928:Organ Specificity; D010052:Ovariectomy; D012741:Sexual Maturation / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D014402:Tuberous Sclerosis / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D047072:Aromatase Inhibitors; D001141:Aromatase; D020123:Sirolimus